Dynamic Plasma Membrane Organization: A Complex Symphony

Abstract

Membrane protein organization is essential for proper cellular functioning and the result of a dynamic exchange between protein monomers, nanoscale protein clusters, and microscale higher-order structures. This exchange is affected by both lipid bilayer intrinsic factors, such as lipid rafts and tetraspanins, and extrinsic factors, such as cortical actin and galectins. Because membrane organizers act jointly like instruments in a symphony, it is challenging to define the 'key' organizers. Here, we posit, for the first time, definitions of key intrinsic and extrinsic membrane organizers. Tetraspanin nanodomains are key organizers that are often overlooked. We discuss how different key organizers can collaborate, which is important to get a full grasp of plasma membrane biology. Open Questions in Plasma Membrane Biology HighlightsNovel definitions are postulated for membrane organizers intrinsic and extrinsic to the lipid bilayer.Membrane protein organization is the result of a dynamic exchange between protein monomers, nanoscale protein clusters, and microscale higher-order structures.Tetraspanins are key membrane organizers that should be considered in future plasma membrane studies.Membrane organizers act together in a dynamic manner like instruments playing a symphony.

Regulation of ADAM10 by the TspanC8 Family of Tetraspanins and Their Therapeutic Potential

“…Tetraspanins are a superfamily of proteins with four transmembrane domains, two extracellular regions and intracellular N-and C-termini (Figure 1) that appear to be present in most multicellular organisms. They function by interacting with specific partner proteins and regulating their intracellular trafficking, lateral mobility, and clustering at the cell surface [33]. There are 33 human tetraspanins, systematically named Tspan1-Tspan33, although cluster of differentiation (CD) nomenclature is more commonly used for those with CD names.…”

Endothelial Cell Behavior Is Determined by Receptor Clustering Induced by Thrombospondin-1

“…As indicated above, integrins are included in tetraspanin-enriched microdomains where they can associate with CD36 and VEGFR-2 in a TSP-1-dependent manner. The αv, α5, β1, and β2 integrins have been reported to be present in these complexes (Hemler, 2014;van Deventer et al, 2020).…”

“…CD36 has been reported to be enriched in lipid rafts and tetraspaninenriched microdomains (Miao et al, 2001;Thorne et al, 2006). The tetraspanins are a family of proteins that contain four transmembrane domains (Hemler, 2014;van Deventer et al, 2020). They undergo homo-and heterotypic association to form distinct regions in the plasma membrane that are enriched in integrins and other membrane proteins.…”

The Context-Dependent Impact of Integrin-Associated CD151 and Other Tetraspanins on Cancer Development and Progression: A Class of Versatile Mediators of Cellular Function and Signaling, Tumorigenesis and Metastasis

“…Despite lack of extracellular ligands or classical domains/motifs for intracellular protein-protein interactions, tetraspanins are capable of carrying out a variety of functional and signaling roles through at least three distinct types of molecular interactions: (1) Imposing a lateral impact on the activation of their cell surface partners; (2) Recruiting signaling molecules via self-association-based micro- or nano-domains; (3) Long-range impact via regulation of secretory vesicles [ 73 , 102 , 103 , 104 , 105 ]. To date, there is a consensus that tetraspanin molecules, together with their molecular partners, form a nano-scale protein complex or molecular network on the plasma membrane, termed as tetraspanin-enriched microdomain (TEM) [ 3 , 8 , 10 , 102 , 106 ].…”